Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Department of Immunology (Professor: Heiichiro Udono, MD,Ph.D) TEL: 086-235-7192 FAX: 086-235-7193 E-mail: [email protected] Ag within the endosome Ag dislocating from the endosome to the cytosol HSP90 The mechanism discriminating between ‘self’ and ‘non-self’ antigen begins with T cell recognition of antigen. We are focusing on the research how cellular proteins and/or extracellular antigens are identified to be degraded by the proteasome because the degradation products act as peptides to be recognized by CD8T cells. Another enthusiasm is on a mechanism of metformin-induced reversion of exhausted CD8T cells, which might be a clue to the resolution for immune exhaustion problem in cancer immunotherapy. The study is also underway as a clinical research in Okayama University Hospital. Department of Immunology MetforminrevertsexhaustedTcellswithintumortissues TCR PD1 LAG3 Tim3 MHC classII PDL1 A2aR Cancer cells adenosine Galectin9 ATP AMP Activationsignals Inhibitorysignals Another part of our study is cancer immunotherapy, focusing on reversion of exhausted CD8 T cells within tumor microenvironment. Cancer vaccine stimulates tumor specific CD8 T cells to migrate into tumors. The tumor infiltrating T cells (TILs), however, rapidly lose their multi-functionality as characterized by decreased production of IL-2, TNFα, IFNγ, followed by apoptosis. The fates might be overcome by approaches like immune checkpoint block with antibodies and/or use of type 2 diabetes medicines such as metformin. The analysis of molecular mechanism is currently underway. In association with clinical studies, we also established a number of monitoring methods by which we could predict clinical prognosis as well as immune status on time. CD8 + T cells recognize naturally processed peptides presented in the context of MHC class I molecules. During viral infection or malignant transformation, any intracellular changes in non-APC (antigen presenting cells) must be reported to CD8 + T cells, which are indispensable in fighting virus-infected cells and cancer cells. For this purpose, Dendritic cells (DCs) internalize neighboring tumor or infected cells, digest them, and then present antigen peptides to CD8 + T cells, referred to as cross-presentation. One of our research goals is to identify the mechanisms of cross-presentation, focusing on the role of the molecular chaperone hsp90, as well as analysis of roles of chaperones in endogenous Ag processing on a perspective of ubiquitination of cellular proteins and digestion by the proteasome. ER-phagosome Sec61 TAP TAP TAP MHC class I MHC class I Model 1 ER peptides Extracellular Ag endosome proteasome HSP90 HSP90 ubiquitin Model 2 proteasome RoleofmolecularchaperonesinAgcrosspresentation Main projects Introduction of our field H. Udono
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Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Department of Immunology (Professor: Heiichiro Udono, MD,Ph.D)
TEL: 086-235-7192 FAX: 086-235-7193 E-mail: [email protected]
Ag within the endosome Ag dislocating from the endosome to the cytosol
HSP90
The mechanism discriminating between ‘self’ and ‘non-self’ antigen begins with T cell recognition of antigen. We are focusing on the research how cellular proteins and/or extracellular antigens are identified to be degraded by the proteasome because the degradation products act as peptides to be recognized by CD8T cells. Another enthusiasm is on a mechanism of metformin-induced reversion of exhausted CD8T cells, which might be a clue to the resolution for immune exhaustion problem in cancer immunotherapy. The study is also underway as a clinical research in Okayama University Hospital.
Department of Immunology
Metformin reverts exhausted T cells within tumor tissues
TCR PD1 LAG3
Tim3
MHC class II PDL1
A2aR
Cancer cells
adenosine
Galectin 9 ATP
AMP
Activation signals
Inhibitory signals
Another part of our study is cancer immunotherapy, focusing on reversion of exhausted CD8 T cells within tumor microenvironment. Cancer vaccine stimulates tumor specific CD8 T cells to migrate into tumors. The tumor infiltrating T cells (TILs), however, rapidly lose their multi-functionality as characterized by decreased production of IL-2, TNFα, IFNγ, followed by apoptosis. The fates might be overcome by approaches like immune checkpoint block with antibodies and/or use of type 2 diabetes medicines such as metformin. The analysis of molecular mechanism is currently underway. In association with clinical studies, we also established a number of monitoring methods by which we could predict clinical prognosis as well as immune status on time.
CD8+ T cells recognize naturally processed peptides presented in the context of MHC class I molecules. During viral infection or malignant transformation, any intracellular changes in non-APC (antigen presenting cells) must be reported to CD8+ T cells, which are indispensable in fighting virus-infected cells and cancer cells. For this purpose, Dendritic cells (DCs) internalize neighboring tumor or infected cells, digest them, and then present antigen peptides to CD8+ T cells, referred to as cross-presentation. One of our research goals is to identify the mechanisms of cross-presentation, focusing on the role of the molecular chaperone hsp90, as well as analysis of roles of chaperones in endogenous Ag processing on a perspective of ubiquitination of cellular proteins and digestion by the proteasome.
ER-phagosome Sec61
TAP
TAP TAP
MHC class I
MHC class I
Model 1
ER
peptides
Extracellular Ag
endosome
proteasome
HSP90
HSP90 ubiquitin
Model 2
proteasome
Role of molecular chaperones in Ag cross presentation
Main projects
Introduction of our field H. Udono
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